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Machine Learning (ML) techniques face significant challenges when predicting advanced chemical properties, such as yield, feasibility of chemical synthesis, and optimal reaction conditions. These challenges stem from the high-dimensional nature of the prediction task and the myriad essential variables involved, ranging from reactants and reagents to catalysts, temperature, and purification processes. Successfully developing a reliable predictive model not only holds the potential for optimizing high-throughput experiments but can also elevate existing retrosynthetic predictive approaches and bolster a plethora of applications within the field. In this review, we systematically evaluate the efficacy of current ML methodologies in chemoinformatics, shedding light on their milestones and inherent limitations. Additionally, a detailed examination of a representative case study provides insights into the prevailing issues related to data availability and transferability in the discipline.

Automated synthesis planning is key for efficient generative chemistry. Since reactions of given reactants may yield different products depending on conditions such as the chemical context imposed by specific reagents, computer-aided synthesis planning should benefit from recommendations of reaction conditions. Traditional synthesis planning software, however, typically proposes reactions without specifying such conditions, relying on human organic chemists who know the conditions to carry out suggested reactions. In particular, reagent prediction for arbitrary reactions, a crucial aspect of condition recommendation, has been largely overlooked in cheminformatics until recently. Here we employ the Molecular Transformer, a state-of-the-art model for reaction prediction and single-step retrosynthesis, to tackle this problem. We train the model on the US patents dataset (USPTO) and test it on Reaxys to demonstrate its out-of-distribution generalization capabilities. Our reagent prediction model also improves the quality of product prediction: the Molecular Transformer is able to substitute the reagents in the noisy USPTO data with reagents that enable product prediction models to outperform those trained on plain USPTO. This makes it possible to improve upon the state-of-the-art in reaction product prediction on the USPTO MIT benchmark., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Two analogues of tolcapone where the nitrocatechol group has been replaced by a 1-hydroxy-2(1 H )-pyridinone have been designed and synthesised. These compounds are expected to have a dual mode of action both beneficial against Parkinson's disease: they are designed to be inhibitors of catechol O -methyl transferase, which contribute to the reduction of dopamine in the brain, and to protect neurons against oxidative damage. To assess whether these compounds are worthy of biological assessment to demonstrate these effects, measurement of their p K a and stability constants for Fe(III), in silico modelling of their potential to inhibit COMT and blood-brain barrier scoring were performed. These results demonstrate that the compounds may indeed have the desired properties, indicating they are indeed promising candidates for further evaluation.